AADACL - Arylacetamide deacetylase like | Elisa - Clia - Antibody - Protein

Background

Arylacetamide deacetylase (AADAC) is an enzyme primarily found in the liver and gastrointestinal tract, encoded by the AADAC gene. Structurally, AADAC belongs to the amidase signature enzyme family, characterized by a conserved catalytic domain involved in amide hydrolysis. Human arylacetamide deacetylase (AADAC) plays a role in drug detoxification or activation. Drug-metabolizing enzymes play roles in the detoxification or activation of drugs and can also cause drug-induced toxicity through the formation of other metabolites. Among the enzymes that metabolize drugs, cytochrome P450. It is responsible for the metabolism of more than 50% of clinical drugs. Other groups known as non-P450 enzymes also play a role in this process. AADAC prefers compounds with relatively small acyl groups. Especially, AADAC prefers compounds with acetyl group. The hydrolytic activities and functional role of AADAC suggest that other members of this protein family may exhibit similar characteristics. The AADAC family comprises five members, including AADAC and four AADAC-like proteins (AADACL1-4). Except for AADACL1, more commonly known as NCEH1, all other members of the AADACL protein family, AADACL2, AADACL3 and AADACL4, have so far been poorly investigated and cannot be concluded to have any functional role.

Structure:

1. Catalytic Domain: AADAC contains a catalytic domain with conserved residues essential for substrate binding and hydrolysis. Within this domain, a catalytic triad comprising a serine, histidine, and aspartate residue is responsible for the nucleophilic attack on the carbonyl carbon of the acetyl group in the substrate.
2. Active Site Architecture: The active site of AADAC is formed by specific amino acid residues that interact with the substrate through hydrogen bonds, electrostatic interactions, and hydrophobic contacts. Substrate specificity and catalytic efficiency are determined by the geometry and chemical properties of the active site residues.
3. Catalytic Mechanism: AADAC employs a two-step catalytic mechanism for amide hydrolysis. In the first step, a nucleophilic attack by the serine residue on the carbonyl carbon of the acetyl group forms an acyl-enzyme intermediate. This intermediate is subsequently hydrolyzed, releasing the deacetylated product and regenerating the active enzyme..

Function:

AADAC catalyzes the hydrolysis of arylacetamide compounds by cleaving the amide bond between the aryl group and the acetyl group. This enzymatic reaction results in the formation of arylamine metabolites and acetic acid, which are more readily excreted from the body through urine or bile.

Biological Significance:

1. Drug Metabolism: AADAC contributes to the biotransformation of drugs and xenobiotics, facilitating their elimination from the body and reducing their potential toxicity.
2. Toxicology: AADAC-mediated metabolism of arylacetamide compounds can influence their pharmacological and toxicological properties, impacting drug efficacy and safety.
3. Individual Variability: Genetic polymorphisms in the AADAC gene can affect enzyme activity and substrate specificity, leading to interindividual variability in drug metabolism and response.

Clinical Issues:

1. Drug Interactions: Variations in AADAC activity and expression levels may influence drug metabolism and response, potentially leading to drug interactions or altered drug efficacy.
2. Toxicity: Dysregulation of AADAC-mediated metabolism of xenobiotics may contribute to drug-induced liver injury or other adverse drug reactions.
3. Pharmacogenetics: Genetic variations in the AADAC gene may influence an individual's susceptibility to drug toxicity or response to pharmacotherapy, highlighting the importance of personalized medicine approaches. Understanding the role of AADAC in drug metabolism is important for predicting drug clearance, optimizing dosage regimens, and minimizing the risk of adverse drug reactions.